子宫内膜癌中超高频突变体PTEN R130G的独特致癌机制

Phosphatase and Tensin Homolog (PTEN) is a critical tumor suppressor frequently mutated in cancers, notably endometrial cancer (EC), where it drives early carcinogenesis. PTEN mutations disrupt lipid phosphatase activity, causing PI3K/AKT/mTOR pathway hyperactivation. However, clinical trials targeting this pathway in advanced EC yield suboptimal outcomes, with PTEN loss showing poorly predictive value for therapeutic response, indicating other mechanisms are involved. TCGA Pan-Cancer Atlas data show a 39.1% co-mutation rate of PTEN and PIK3CA in EC, much higher than the 3.6% pan-cancer rate, challenging the idea of mutual exclusivity in driver mutations within the same pathway. PTEN missense mutations are most common in EC (41.44%), with R130 as a hotspot, especially among PIK3CA-mutant patients (45.28%), while other cancers with frequent PTEN mutations show much lower R130 rates. These findings suggest PTEN R130 missense mutants undergo positive selection and may have unique oncogenic effects in EC.To characterize these mutants, a Tet-on inducible system in PTEN-null SPAC-1-S EC cells compared wild-type PTEN (PTEN WT ), loss of function mutant PTEN R173C , and ultrahigh frequency mutant PTEN R130G . PTEN WT suppressed proliferation, PTEN R173C showed reduced tumor suppressive activity, while PTEN R130G increased proliferation, indicating a PTEN WT -independent tumor-promoting function. In MFE 296 cells with PTEN R130Q/N332fs mutations, knockdown of PTEN R130Q suppressed proliferation, providing functional evidence that PTEN R130G has PTEN WT -independent oncogenic activity in EC. To elucidate the underlying mechanisms, we performed quantitative proteomic and BioSITe analyses in SPAC-1-S cells inducibly expressing PTEN WT or PTEN R130G , enabling comprehensive mapping of the unique signaling alterations specific to this ultrahigh-frequency PTEN R130G mutant. Our initial analysis revealed that PTEN WT induction caused broad transcriptional suppression of oncogenic and structural pathways, including MAPK/ERBB, focal adhesion, ECM-receptor interaction, and lysosomal function, consistent with restored tumor-suppressive activity. In contrast, PTEN R130G induction led to a distinct transcriptional response; while partially repressing lysosomal and adhesion pathways, stress-adaptive and metabolic programs like TGF-beta signaling and glutathione metabolism remained active or were reactivated. These results suggest PTEN R130G not only loses PTEN's inhibitory functions but may gain new transcriptional and metabolic activities that promote cell survival and tumor progression. Overall, our analysis indicates wildtype PTEN restores signaling restraint, while PTEN R130G reprograms the transcriptome toward a pro-cancer, stress-resilient state, suggesting a gain-of-function oncogenic role.